The present invention relates to novel 4-(N-substituted amino)-2-butynyl-1-ureas and thioureas and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention are centrally acting muscarinic agents useful in treating the symptoms of cognitive decline in an elderly patient.
Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well accepted. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least ten percent of persons over sixty years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
Many of the symptoms of cognitive disorders, especially impaired memory, are associated with decreased acetylcholine synthesis and the impairment of cholinoreceptive neurons In the hippocampus and cerebral cortex of patients suffering from primary degenerative dementia for example, the level of the enzyme choline acetyltransferase (CAT) can be reduced as much as ninety percent (see Davies, P., et al, The Lancet, 2, page 1403 (1976); Perry, E. K., et al, Journal of Neurological Sciences, 34, pages 247 to 265 (1977); and White, P., et al, The Lancet, 1, pages 668 to 670 (1977)).
Since CAT catalyzes the synthesis of acetylcholine from its precursors choline and acetyl coenzyme A, the loss of CAT reflects the loss of cholinergic or acetylcholine-releasing nerve ending in the hippocampus and cerebral cortex. There is abundant evidence that cholinergic terminals in the hippocampus are critically important for memory formation.
The cholinergic hypothesis suggests that drugs which restore acetylcholine levels or cholinergic function (i.e., cholinomimetic) are effective in correcting this deficit in neurotransmitter chemical and provide treatment of the memory impairment symptom of cerebral insufficiency. Considerable biochemical, pharmacological, and electrophysiological evidence supports the hypothesis that deficits in the cholinergic system underlie geriatric cognitive dysfunction (Peterson, C. and Gibson, G. E., Neurobiology of Aging, 4, pages 25 to 30 (1983)). Aged humans and nonhuman primates with decreased cognition show improved memory when they are treated, for example, with acetylcholinesterase inhibitors such as physostigmine. These agents increase the available supply of synaptic acetylcholine by inhibiting its hydrolysis.
Aminopyridines such as 3,4-diaminopyridine ameliorate age-related cognitive deficits by increasing the release of acetylcholine from presynaptic nerve terminals, thus increasing synaptic acetylcholine (see Davis, H. P., et al, Experimental Aging Research, 9, pages 211 to 214 (1983)).
It has been known for some time that the natural alkaloid, muscarine, has the ability to act relatively selectively at autonomic effector cells to produce qualitatively the same effect as acetylcholine. Two other agents, pilocarpine and oxotremorine, have the same principal sites of action as muscarine and acetylcholine and are thus classified as having "muscarinic" action. Although these agents are of great value as pharmacological tools, present clinical use is largely restricted to the use of pilocarpine as a miotic agent.
Oxotremorine (1-pyrrolidino-4-(2-oxopyrrolidino)-2-butyne) was discovered while exploring the pharmacologic actions of tremorine. During the course of screening drugs in mice, it was observed that tremorine (1,4-dipyrrolidino-2-butyne) produced a profound tremor of the head and limbs lasting for more than one hour (see Everett, G. M., Science, 124, page 79 (1956)). It was later discovered that tremorine is converted to an active metabolite, oxotremorine, which is responsible for its pharmacological properties.
A series of N-(4-amino-2-butynyl)-N-alkylcarboxamides useful as central nervous system stimulants is disclosed in U.S. Pat. No. 3,354,178.
A series of N-(4-amino-2-butynyl)imides useful as central nervous system stimulants and depressants is disclosed in U.S. Pat. No. 4,065,471.
The central and peripheral activity of a series of acetylenic amines related to oxotremorine is disclosed by Bebbington, A., et al, British Journal of Pharmacology 26, pages 56 to 67 (1966). The pharmacological properties of additional structural modifications of oxotremorine are disclosed by Neumeyer, J. L., et al, Journal of Medicinal Chemistry 10, pages 615 to 620 (1967).
However, none of the compounds disclosed in the aforementioned references suggests the combination of structural variations of the compounds of the present invention described hereinafter. Furthermore, the aforementioned compounds are not disclosed for treating the symptoms of cognitive decline in an elderly patient.